This SBIR Phase II grant will support the commercial development of an injectable biological product candidate, a unique proprietary recombinant humanized anti-factor XI monoclonal antibody (AXIMAB), towards an investigational new drug (IND) application. The lead indication for AXIMAB is severe bacterial sepsis, which is a major cause of mortality in hospitalized patients. Sepsis-associated disseminated intravascular coagulation (DIC) contributes to organ perfusion deficits, ischemia, and a systemic inflammatory response syndrome (SIRS). Antithrombotic drugs may effectively limit septic DIC; however, their antithrombotic doses can produce severe bleeding side-effects. Apart from antibiotics, the only FDA-approved treatment for severe sepsis is the anticoagulant enzyme recombinant activated protein C (APC, Xigris(R)), but the bleeding side-effects of APC can often outweigh its benefits. There is a major unmet medical need for safer and more effective treatments, and our product candidate addresses this need by providing an alternative to APC. In primates, anticoagulation with our anti-FXI antibodies 1A6 or 14E11 is safe and antithrombotic. Our SBIR Phase I data demonstrate that anticoagulation with our universal anti-FXI antibody 14E11 improves the survival of polymicrobial peritonitis in mice, while reducing the inflammatory and coagulation responses to sepsis, and our Phase II preliminary studies show a survival benefit for mice treated with 14E11 during septic Listeriosis. We have demonstrated that 14E11 selectively inhibits factor XI (FXI) activation by factor XIIa (FXIIa). Since FXI activation by FXIIa is independent of hemostasis, using 14E11 for blocking prothrombotic FXI activation by FXIIa could translate into therapeutic anticoagulation with unprecedented safety. Since no comparable product exists, AXIMAB 14E11 would compete successfully with APC and other anticoagulants under development, including activated FXI inhibitors, and therefore has a very large market potential. The Specific Aims are to 1. Evaluate the efficacy of AXIMAB 14E11 treatment in experimental microbe-specific sepsis; 2. Determine the activity and stability of GMP-grade humanized recombinant AXIMAB batches; and 3. Determine the toxicity of humanized AXIMAB in preclinical studies. Success of this Phase II project will support the advancement of AXIMAB into clinical studies. PUBLIC HEALTH RELEVANCE: Occlusion of blood vessels by clots significantly contributes to the high mortality rate of sepsis, and drugs that are effective against blood clots in vessels (antithrombotic drugs or blood thinners) have only limited utility because they also aggravate the bleeding tendency (coagulopathy) that characterizes severe sepsis. Apart from antibiotics, the only FDA-approved treatment for severe sepsis is the antithrombotic enzyme recombinant activated protein C (APC, Xigris(R)), but bleeding side-effects often outweigh its benefits. The lack of safe and effective sepsis treatments represents a major unmet medical need that we address with the development of a new antithrombotic molecule, a therapeutic anti-factor XI antibody that does not cause bleeding and thus provides a safe alternative to APC for treating the coagulopathic complications of sepsis. 1